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NEW YORK CITY—Autologous transplant for multiple myeloma has become safe enough so that the principal role for allogeneic transplant appears to be in salvage therapy for relapsed or refractory disease--and even then, it should be used mainly in the context of a clinical trial.

So said Sergio A. Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memorial Sloan-Kettering Cancer Center, speaking here at the Lymphoma & Myeloma International Congress on Hematologic Malignancies, hosted by the Center for Lymphoma and Myeloma, Weill Cornell Medical College, New York-Presbyterian Hospital.

“The bar has gotten significantly higher since the results of autologous transplants—particularly with maintenance lenalidomide—have improved to where it gets harder and harder to justify doing [allograft] on all patients,” Dr. Giralt said, in a telephone interview after the meeting. “Even in the best of hands there is still a 1-in-10 chance of dying from complications of treatment.”

Dr. Giralt, who moved to Memorial Sloan-Kettering a few months ago after 21 years at the University of Texas MD Anderson Cancer Center, said much of the transplant trial data in the literature were from a time when autologous transplant was considered the most intensive therapy for myeloma.

“We were thinking [at that time] that only 40% of patients would achieve a major response, but that was in the context of alkylator-based induction, high-dose melphalan, and no maintenance,” he said. “Now the paradigm has changed [in favor of autologous transplant].”

Modern induction therapy includes an immune modulatory drug, a proteosome inhibitor, and steroids followed by consolidation therapy with either one or two cycles of high-dose melphalan, and finally autologous transplant support followed by maintenance therapy, Dr. Giralt said.

“With maintenance therapy there is the possibility of reducing risk of relapse. Whether patients will live longer or not we don't know.”

Maintenance today includes an immune modulatory drug, which was initially thalidomide until two studies showed that lenalidomide improves progression-free survival.

“And that's where the bar lies today,” he said. “As we talk with patients, we can say that with the single autologous transplant—the most common transplant performed in the US—followed by lenalidomide daily, the expectation after three years of event-free survival is still to be cured.”

He said he expects that median event-free survival for these patients after autologous transplant will be beyond five years and that 90%-plus of patients will be alive three years after their transplant, compared with allogeneic transplant, which even in the best of hands has a non-relapse mortality rate of approximately a year.

Dr. Giralt said multiple studies looking at the role of reduced intensity regimens have shown that they reduce transplant-related mortality.

On the other hand, there have been no studies showing that patients assigned to an allograft because HLA-compatible donors were available actually did better than patients assigned to autologous transplant.

“The problem with these studies is that the number of patients is exceedingly small, and were not powered to see a benefit of even 15 or 20 percent,” he said.

But even larger studies with median follow-ups of five years or more are finding that some 30% of these patients remain alive without disease progression after allogeneic transplant.

“Is that good enough? Would that make me tell a 55-year-old with standard-risk myeloma that ‘I think you should undergo an allogeneic transplant because you have an HLA-compatible donor'?” he asked rhetorically.

“And would that mean I tell my 55-year-old there is a 40% chance of having chronic graft-versus-host disease and requiring immune suppressive therapy for the rest of your life? In the case of standard risk patients, probably not, but we're still waiting for what we call the definitive trial.”

Clinical Trials

Dr. Giralt said that he thinks that allogeneic transplants should be done primarily in clinical trials, and that he would like to see the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) and the cooperative groups develop national trials together that exploit the potential beneficial effects of a graft-versus-myeloma effect while reducing the deleterious effect of graft-versus-host disease.

The results from the BMT-CTN 0102 study—of which he is a coauthor—were scheduled to be presented in early December at the American Society of Hematology Annual Meeting. The trial compares tandem autologous transplant with single autologous transplant plus non-myeloablative allogeneic transplant in patients with standard risk myeloma.

Since the abstracts from the meeting were still under embargo at the time of the interview with Dr. Giralt, he couldn't discuss the results further, but said that one could start imagining the impact of this study on the field of allogeneic transplant.

The subsequently released results, though, scheduled to be presented by Edward A. Stadtmauer, MD, of Abramson Cancer Center of the University of Pennsylvania showed that a planned secondary analysis of a cohort of high-risk myeloma patients had equivalent three-year progression-free and overall survival for tandem autologous stem cell transplants and HLA-matched sibling non-myeloablative allogeneic transplant (auto-allo) in both intent-to-treat and as-treated analyses.

However, the authors said, trends in late progression-free survival and time to progression/relapse suggest that further follow-up is needed before final conclusions can be made about the utility of auto-allo in this cohort of high-risk patients. The researchers concluded that the study shows the feasibility of an allogeneic hematopoietic stem cell transplant approach for high-risk myeloma patients and may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects.

“We have to recognize that unless it is strongly positive in one way or the other, the number of allogeneic transplants that will be performed for frontline treatment for myeloma will probably decrease,” Dr. Giralt said before the ASH meeting. “But I continue to think that the number of allogeneic transplants that will be explored for salvage therapy will actually increase.”

Allograft for salvage “still surprises me,” Dr Giralt said. He described one of his patients, a 37-year-old man who underwent a transplant at MD Anderson in 2000. The patient had a very long remission after initial therapy, had relapse, and then did not respond to salvage therapy with bortezomib. He did have a partial response to lenalidomide and then went on to an autologous transplant for salvage, but relapsed again.

“At that time we gave combination chemotherapy and an allogeneic transplant, and this patient now remains in remission more than three years after having had only a partial response to combination chemotherapy, and is immune fixation negative without graft-versus-host disease. So I still think there is a role for this treatment modality in patients, particularly in the setting of salvage.”